U.S. patent number 5,536,729 [Application Number 08/301,179] was granted by the patent office on 1996-07-16 for rapamycin formulations for oral administration.
This patent grant is currently assigned to American Home Products Corporation. Invention is credited to Thomas W. Leonard, Robert P. Waranis.
United States Patent |
5,536,729 |
Waranis , et al. |
July 16, 1996 |
Rapamycin formulations for oral administration
Abstract
The present invention provides novel oral rapamycin formulations
which have, per 100 ml of the formulation, from about 0.01 grams to
about 5.0 grams of rapamycin, from about 0.05% to about 10% by
volume of surfactant, and from about 75% to about 99.95% by volume
of a solution of phospholipid or lecithin in which the phospholipid
or lecithin therein is 40% to 75% by weight.
Inventors: |
Waranis; Robert P. (Chazy,
NY), Leonard; Thomas W. (Willmington, NC) |
Assignee: |
American Home Products
Corporation (Madison, NJ)
|
Family
ID: |
26827654 |
Appl.
No.: |
08/301,179 |
Filed: |
September 9, 1994 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
129529 |
Sep 30, 1993 |
|
|
|
|
Current U.S.
Class: |
514/291 |
Current CPC
Class: |
A61P
35/00 (20180101); A61K 47/24 (20130101); A61P
37/06 (20180101); A61K 47/18 (20130101); A61P
31/10 (20180101); A61K 9/4858 (20130101); A61K
31/435 (20130101); A61P 31/04 (20180101); A61P
37/00 (20180101); A61P 31/02 (20180101); A61K
9/1277 (20130101); A61K 47/10 (20130101); A61K
47/26 (20130101) |
Current International
Class: |
A61K
31/435 (20060101); A61K 47/16 (20060101); A61K
47/24 (20060101); A61K 47/00 (20060101); A61K
9/48 (20060101); A61K 47/18 (20060101); A61K
9/127 (20060101); A61K 47/10 (20060101); A61K
47/26 (20060101); A61K 031/445 () |
Field of
Search: |
;514/291,76 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0041795 |
|
Dec 1981 |
|
EP |
|
0428169 |
|
May 1991 |
|
EP |
|
0444659 |
|
Sep 1991 |
|
EP |
|
Other References
Physicians' Desk Reference, 45th ed., 1991, pp. 2119-2122, Medical
Economics Company, Inc. .
Physicians' Desk Reference, 45th ed., 1991, pp. 785-787, Medical
Economics Company, Inc. .
Luke et al., Effects of Cyclosporine on the Isolated Perfused Rat
Kidney, Transplantation, vol. 43, No. 6, pp. 795-799, 1987. .
Venkataram, et al., Pharmacokinetics of Two Alternative Dosage
Forms for Cyclosporine: Liposomes and Intralipid, Journal of
Pharmaceutical Sciences, vol. 79, No. 3, pp. 216-219, 1990. .
Thiel, et al., Acutely Impaired Renal Function During Intravenous
Administration of Cyclosporine A: A Cremaphore Side-Effect,
Clinical Nephrology, vol. 25, Suppl. No. 1, pp. S40-S42, 1986.
.
Honbo, et al., The Oral Dosage Form of FK-506, Transplantation
Proceedings, vol. XIX, No. 5, Suppl. 6, pp. 17-22, 1987. .
Stepkowski, et al., Rapamycin, A Potent Immunosuppressive Drug for
Vascularized Heart, Kidney, and Small Bowel Transplantation in the
Rat, Transplantation, vol. 51, No. 1, pp. 22-24, 1991. .
Kahan, et al., Synergistic Interactions of Cyclosporine and
Rapamycin to Inhibit Immune Performances of Normal Human Peripheral
Blood Lymphocytes In Vitro, Transplantation, vol. 51, No. 1, pp.
232-237, 1991. .
Intl. Pharm. Abstracts--FK--506, Immunosuppressant for the 1990s,
Macleod, et al., Lancet, 337, pp. 25-27, Jan. 5, 1991. .
Intl. Pharm. Abstracts, FK-506: Discussion of a New Investigationsl
Drug, C. G. Forde, ASHP Midyear Clinical Meeting, 25, p. 446D, Dec.
1990. .
Intl. Pharm. Abstracts, FK-506, Kidney Transplantation Under FK
506, Starzl, et al., JAMA, 264, pp. 63-67, Jul. 4, 1990. .
Intl. Pharm. Abstrcts-FK-506 In Steroid--Resistant Focal Sclerosing
Glomerulonephritis of Childhood, McCauley, et al., Lancet, 335, p.
674, Mar. 17, 1990. .
Intl. Pharm. Abstracts, New Drug Could Replace Cyclosporin in
Transplant Drug Therapy, Anon, Am. Pharm. NS, 30, 16, Jan. 1990.
.
Intl. Pharm. Abstracts, Treatment of Cyclosporin Induced
Hemolytic-Uremic Syndrome with FK-506, McCauley, et al., Lancet, 2,
1516, Dec. 23-30, 1989. .
Intl. Pharm. Abstracts-FK-506 for Liver, Kidney, and Pancreas
Transplantation; Starzl, et al., Lancet, 2, 1000-1004, Oct. 28,
1989..
|
Primary Examiner: Spivack; Phyllis G.
Attorney, Agent or Firm: Eck; Steven R.
Parent Case Text
This application is a continuation-in-part of Ser. No. 08/129,529,
now abandoned, filed Sep. 30, 1993.
Claims
What is claimed:
1. A composition comprising, per 100 ml of composition, from about
0.01 gram to about 5.0 grams of rapamycin, and a solvent system,
said solvent system comprising from about 0.05 to 10% by volume of
a surfactant, and from about 75 to 99.95% by volume of a
phospholipid solution in which the phospholipid therein is 40% to
75% by weight.
2. The composition of claim 1 wherein the phospholipid solution is
a lecithin solution.
3. A composition of claim 1 containing from about 0.03 gram to
about 1.0 gram of rapamycin per 100 ml, and a solvent system
containing from about 0.10 ml to about 5 ml of surfactant per 100
ml, and from about 90 to about 99.95 ml of a phosholipid solution,
the solution containing from about 40% to about 70% by weight of
phospholipid in a suitable solvent, per 100 ml.
4. The composition of claim 1 which contains, per 100 ml
composition, from about 0.03 gram to about 0.8 grams rapamycin,
from about 0.10 ml to about 5 ml of surfactant, and from about 95
to about 99.9 ml of a 50% phospholipid solution.
5. The composition of claim 1 which contains, per 100 ml
composition, from about 0.05 grams to about 0.5 grams rapamycin,
from about 0.5 ml to about 5 ml of surfactant, and from about 95 to
about 99.5 ml of a 50% phospholipid solution.
6. The composition of claim 1 which contains, per 25 ml
composition, 0.025 g of rapamycin, 0.270 g of surfactant, and a 50%
phospholipid solution q.s. to 25 ml.
7. The composition of claim 1 which contains, per 25 ml
composition, 0.125 g of rapamycin, 0.270 g of surfactant, and a 50%
phospholipid solution q.s. to 25 ml.
8. The composition of claim 1 which contains, per 100 ml
composition, 1.0 g of rapamycin, 1.0 ml of surfactant, and a 50%
phospholipid solution q.s. to 100 ml.
9. The composition of claim 1 which is contained within a
pharmaceutically acceptable starch capsule.
10. The composition of claim 1 which is contained within a
pharmaceutically acceptable gelatin capsule.
11. The composition comprising, per 100 ml composition, from about
0.01 grams to about 5.0 grams of rapamycin and a solvent system
comprising:
a) from about 0.05% to about 10% by volume of surfactant,
b) from about 0.1% to about 50% by volume of absolute ethanol,
and
c) from about 40% to about 99.85% by volume of a phospholipid
solution, the phospholipid solution being from about 40% to about
75% by weight phospholipid.
12. The composition of matter of claim 11 wherein the phospholipid
solution is a lecithin solution.
13. The composition of claim 11 comprising, per 100 ml composition,
from about 2.0 to about 3.0 grams of rapamycin and a solvent system
comprising:
a) from about 3% to about 7.5% by volume of surfactant,
b) from about 5% to about 20% by volume of absolute ethanol,
and
c) from about 40% to about 92% by volume of a phospholipid
solution, the phospholipid solution being from about 40% to about
60% by weight phospholipid.
14. The composition of claim 11 comprising, per 100 ml composition,
2.5 grams of rapamycin, 5.0 ml of surfactant, about 12.67 ml of
absolute ethanol, and a 50% phospholipid solution q.s to 100 ml.
Description
This invention relates to formulations or compositions containing
rapamycin, or pharmaceutically acceptable salts of rapamycin, which
are useful in oral administrations for inducing immunosuppression
and for treating transplantation rejection, host vs. graft disease,
autoimmune diseases, diseases of inflammation, solid tumors, fungal
infections, adult T-cell leukemia/lymphomas and hyperproliferative
vascular disorders.
BACKGROUND OF THE INVENTION
Rapamycin is a macrolide antibiotic produced by Streptomyces
hygroscopicus which was discovered first for its properties as an
antifungal agent. It adversely affects the growth of fungi such as
Candida albicans and Microsporum gypseum. Rapamycin, its
preparation and its antibiotic activity were described in U.S. Pat.
No. 3,929,992, issued Dec. 30, 1975 to Surendra Sehgal et al. In
1977 Martel, R. R. et al. reported on immunosuppressive properties
of rapamycin against experimental allergic encephalitis and
adjuvant arthritis in the Canadian Journal of Physiological
Pharmacology, 55, 48-51 (1977). In 1989, Calne, R. Y. et al. in
Lancet, 1989, no. 2, p. 227 and Morris, R. E. and Meiser, B. M. in
Medicinal Science Research, 1989, No. 17, P. 609-10, separately
reported on the effectiveness of rapamycin in inhibiting rejection
in vivo in allograft transplantation. Numerous articles have
followed describing the immunosuppressive and rejection inhibiting
properties of rapamycin, and clinical investigation has begun for
the use of rapamycin in inhibiting rejection in transplantation in
man.
Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with
picibanil (U.S. Pat. No. 4,401,653) has been shown to have
antitumor activity. R. Martel et al. [Can. J. Physiol. Pharmacol.
55, 48 (1977)] disclosed that rapamycin is effective in the
experimental allergic encephalomyelitis model, a model for multiple
sclerosis; in the adjuvant arthritis model, a model for rheumatoid
arthritis; and effectively inhibited the formation of IgE-like
antibodies.
The immunosuppressive effects of rapamycin have been disclosed in
FASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic
molecules, also have been shown to be effective as
immunosuppressive agents, therefore useful in preventing transplant
rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R. Y. Calne
et al., Lancet 1183 (1978); and U.S. Pat. No. 5,100,899].
Rapamycin has also been shown to be useful in preventing or
treating systemic lupus erythematosus [U.S. Pat. No. 5,078,999],
pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin dependent
diabetes mellitus [Fifth Int. Conf. Inflamm. Res. Assoc. 121
(Abstract), (1990)], and smooth muscle cell proliferation and
intimal thickening following vascular injury [Morris, R. J. Heart
Lung Transplant 11 (pt. 2): 197 (1992)].
Mono- and diacylated derivatives of rapamycin (esterified at the 28
and 43 positions) have been shown to be useful as antifungal agents
(U.S. Pat. No. 4,316,885) and used to make water soluble prodrugs
of rapamycin (U.S. Pat. No. 4,650,803). Recently, the numbering
convention for rapamycin has been changed; therefore according to
Chemical Abstracts nomenclature, the esters described above would
be at the 31- and 42- positions. U.S. Pat. No. 5,118,678 discloses
carbamates of rapamycin that are useful as immunosuppressive,
anti-inflammatory, antifungal, and antitumor agents. U.S. Pat. No.
5,100,883 discloses fluorinated esters of rapamycin. U.S. Pat. No.
5,118,677 discloses amide esters of rapamycin. U.S. Pat. No.
5,130,307 discloses aminoesters of rapamycin. U.S. Pat. No.
5,117,203 discloses sulfonates and sulfamates of rapamycin. U.S.
Pat. No. 5,194,447 discloses sulfonylcarbamates of rapamycin.
U.S. Pat. No. 5,100,899 (Calne) discloses methods of inhibiting
transplant rejection in mammals using rapamycin and derivatives and
prodrugs thereof. Other chemotherapeutic agents listed for use with
rapamycin are azathioprine, corticosteroids, cyclosporin (and
cyclosporin A), and FK-506, or any combination thereof.
The primary immunosuppressive agent presently used for inhibiting
rejection in the allograft transplantation of organs in man is
cyclosporine (Sandimmune.RTM.). Cyclosporine is a cyclic
polypeptide consisting of 11 amino acids. The intravenous
injectable formulation of Sandimmune.RTM. (IV) is a sterile ampul
containing, per ml, 50 mg of cyclosporine, 650 mg of Cremophor.RTM.
EL and alcohol Ph Helv. (32.9% by volume) (under nitrogen). For
administration this mixture is diluted further with 0.9% Sodium
Chloride Injection or 5% Dextrose Injection before use.
(Physicians' Desk Reference, 45th ed., 1991, pp. 1962-64, Medical
Economics Company, Inc.) The macrolide molecule designated FK506,
which has certain structural similarities to rapamycin, is also
currently undergoing clinical investigation for inhibiting
rejection in allograft organ transplantation in man. FK506 is
isolated from Streptomyces tsuskubaensis and is described in U.S.
Pat. No. 4,894,366 to Okuhara et al., issued January 16, 1990 R.
Venkataramanan et al., in Transplantation Proceedings, 22, No. 1,
Suppl., 1 pp 52-56 (February 1990), report that the intravenous
injectable formulation of FK506 is provided as a 10 mg/ml solution
of FK506 in polyoxyethylated castor oil (HCO-60, a surfactant) and
alcohol. The intravenous preparation must be diluted with saline or
dextrose and administered as an infusion for 1 to 2 hours.
The Physicians' Desk Reference (45th ed., 1991, p. 2119, Medical
Economics Company, Inc.) lists cyclosporine under the
Sandimmune.RTM. tradename as available in 25 mg and 100 mg strength
capsules and as an oral solution in 50 ml bottles. The 25 mg
capsules contain 25 mg cyclosporine, USP, and alcohol, USP
dehydrated, at a maximum of 12.7% by volume. The 100 mg capsules
contain cyclosporine, USP, 100 mg and alcohol, USP dehydrated, at a
maximum 12.7% by volume. Inactive ingredients in the oral capsules
are corn oil, gelatin, glycerol, Labrafil M 2125 CS
(polyoxyethylated glycolysed glycerides), red iron oxide, sorbitol,
titanium dioxide, and other ingredients. The oral solution is
available in 50 mg bottles containing cyclosporine, USP, 100 mg and
Ph. Helv. alcohol at 12.5% by volume dissolved in olive oil, Ph.
Helv./Labrafil M 1944 CS (polyoxyethylated oleic glycerides)
vehicle which must be diluted further with milk, chocolate milk or
orange juice before oral administration.
Azathioprine (available from Burroughs Wellcome Co., Research
Triangle Park, N.C., under the tradename Imuran.RTM.) is another
orally administered immunosuppressive agent prescribed alone or in
conjunction with other immunosuppressive agents. The Physicians'
Desk Reference (45th ed., 1991, pp. 785-787, Medical Economics
Company, Inc.) lists azathioprine as
6-[1-methyl-4-nitroimidazol-5-yl)thio]purine, which is provided for
oral administration in scored tablets containing 50 mg azathioprine
and the inactive ingredients lactose, magnesium stearate, potato
starch, povidone, and stearic acid.
DESCRIPTION OF THE INVENTION
Methods of drug delivery are designed to deliver an acceptable
dosage of the medication to the patient. In the case of oral
formulations, it is highly desirable to provide a dosage form which
meets this criteria and which can be effectively administered,
preferably self-administered, in either clinical or non-clinical
situations. The present invention concerns formulations useful in
the oral administration of rapamycin. Rapamycin has been shown to
possess immunosuppressive, antifungal and antiinflammatory activity
in vivo and to inhibit thymocyte proliferation in vitro. Therefore,
these formulations are useful in the treatment of Candida albicans
infections, diseases of inflammation and transplant rejection
autoimmune diseases, including lupus, rheumatoid arthritis,
diabetes melitus, multiple sclerosis, etc.
Because the formulations disclosed herein contain rapamycin, they
are considered to have antitumor, antifungal and antiproliferative
activities. As such, the formulations of this invention are useful
in the treatment of transplantation rejection, such as heart,
kidney, liver, bone marrow and skin transplants; autoimmune
diseases such as lupus, rheumatoid arthritis, diabetes mellitus,
myasthenia gravis and multiple sclerosis; diseases of inflammation
such as psoriasis, dermatitis, eczema, seborrhea, inflammatory
bowel disease and eye uveitis; solid tumors; fungal infections; and
hyperproliferative vascular diseases, such as restenosis. The
present invention, therefore, also provides formulations useful for
inducing immunosuppression in a mammal in such need. Such
inducements would comprise administering to said mammal an
immunosuppressive amount of one or more of the formulations
discussed herein.
The formulations of the present invention may be produced as a one
component, ready to use solution of rapamycin in a non-aqueous
system consisting of a solvent, surfactant and a phospholipid
solution to produce an acceptable dosage form for chronic use in
association with immunosuppressant therapy, as well as antitumor,
antifungal and antiproliferative activities. The one component
system may be adjusted to eliminate the solvent in cases where the
drug concentration can be solubilized in the remaining ingredients.
The invention may also be produced alternatively as a two component
system either comprised of a dry component fill of 100% rapamycin
and diluent or a drug concentrate and diluent. Other filler
materials, such as lactose or mannitol, may be used as a portion of
the dry component of such systems.
In general, the formulations or compositions of the present
invention include those containing combinations of a) rapamycin, b)
surfactant, and c) lecithin or phospholipid solution in the
following concentrations (per 100 ml formulation);
a) rapamycin at a concentration of from about 0.01 grams to about
5.0 gram per 100 ml; and
b) a solvent system comprising:
i) Surfactant at a concentration of from about 0.05 ml to about 10
ml per 100 ml; and
ii) from about 75 to about 99.95 ml per 100 ml of a lecithin or a
phosholipid solution containing from about 40 to about 75 percent
of lecithin or phospholipid by weight in one or more suitable
solvents.
More preferred formulations of the present invention include those
having the following concentration (per 100 ml formulation):
a) rapamycin at a concentration of from about 0.03 grams to about
1.0 gram per 100 ml;
b) Surfactant at a concentration of from about 0.10 ml to about 5
ml per 100 ml; and
c) from about 90 ml to about 99.9 ml per 100 ml of a lecithin or a
phosholipid solution containing from about 40 percent to about 70
percent by weight of lecithin or phospholipid in one or more
suitable solvents.
A most preferred formulation of the present invention includes
those formulations having concentrations of ingredients within the
following ranges:
a) rapamycin at a concentration of from about 0.05 grams to about
0.5 grams per 100 ml;
b) Surfactant at a concentration of from about 0.5 ml to about 5 ml
per 100 ml; and
c) from about 95 to about 99.5 ml per 100 ml of a lecithin or a
phosholipid solution containing from about 40 to about 60 percent
by weight of lecithin or phospholipid in one or more suitable
solvents.
The rapamycin dosage requirements for these formulations may vary
depending upon the severity of the symptoms presented and the
particular subject being treated. Projected daily oral dosages of
the compounds of this invention, per kilogram of patient body
weight, would be 0.005-75 mg/kg, preferably between 0.01-50 mg/kg,
and more preferably between 0.05-10 mg/kg.
Treatment will generally be initiated with small dosages less than
the optimum dose of the compound. Thereafter the dosage is
increased until the optimum effect under the circumstances is
reached. Precise dosages will be determined by the administering
physician based on experience with the individual subject treated.
In general, the formulations of this invention are most desirably
administered at a concentration that will afford effective results
without causing any harmful or deleterious side effects.
The present formulations may be administered to the patient by the
means generally used for oral liquid medications. They may be
taken, by themselves, or they may be dispersed in a liquid, such as
water or juices. The formulations may also be capsulized, such as
in pharmaceutically acceptable starch capsules or soft elastic
gelatin (SEG) capsules. Rapamycin oral may be dispersed into water
for dosing in the range of about 1 part of formula into about 9
parts water downward to about 1 part of formula into about 499
parts water by mixing for a minimum of about 60 seconds. This
dispersion may be used over about a 1 hour period with mixing prior
to dosing.
A number of solvents, other than those listed below, can be used to
solubilize the drug(s) of the formulation covered herein. These
include, but are not limited to, dimethylacetamide, ethanol,
dimethylformamide, glycerin, polyethylene glycol, t-butanol, and
propylene glycol. It is understood that the amounts of these
solvents can be raised in conjunction with the drug
concentration(s). Alternately, the amounts of the solvents can be
reduced in conjunction with the drug concentrations and, if drug
solubility permits, the lecithin, alone, can act as the
solvent.
Surfactants that may be used with the present formulations include,
but are not limited to, Polysorbate 20 (polyoxyethylene 20 sorbitan
monolaurate), Polysorbate 60, Span 80.RTM. Sorbitan Oleate, a
product of ICI Americas, Wilmington, Del., the Cremophor.RTM.
surfactants produced by the BASF Corporation, Parsippany, N.J., and
Polysorbate 80, which is defined by the Merck Index, 11th Edition,
published by Merck & Co., Inc., Copyright 1989, on page 1254 as
Sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivatives,
polyoxyethylene (20) sorbitan mono-oleate, Sorbitan mono-oleate
polyoxyethylene, Softate, Tween 80, among others, and indicates an
oleate ester of sorbitol and its anhydrides copolymerized with
approximately 20 moles of ethylene oxide for each mole of sorbitol
and sorbitol anhydrides. Polysorbate 80 is the surfactant preferred
for use with the present invention.
A number phospholipid solutions may be used in the present
formulations. It is preferred that the phospholipid solution of the
present formulations comprises a lecithin solution. Lecithin is a
general term for phosphatidylcholine or a mixture of various
diglycerides of stearic, palmitic, and oleic acids, linked to the
choline ester of phosphoric acid. Various types of lecithin or
lecithin sourced products (such as separated phospholipids), either
alone or mixed with various solvents, can be used as the final
ingredient of the formulations mentioned above. These lecithin
ingredients can include, for example, Alcolec.RTM. lecithin,
produced by the American Lecithin Company, Danbury, Conn., Phosal
50 PG propylene glycol and lecithin, Phosal 50 MCT
phosphatidylcholine and medium chained triglycerides, and
Phospholipan 90.RTM. lecithin, all of which are produced by
Nattermann Phospholipid GMBH, Colone, Germany, the Centrophil.RTM.
and Centrophase.RTM. lecithins produced by Central Soya, Fort
Wayne, Ind. It is preferred that the phospholipid solutions used in
the present formulation have at least a 50% concentration of
phospholipid. More particularly, it is preferred that the
phospholipid solutions used with the present formulations be
lecithin products or solutions having at least 50%
phosphatidylcholine. It is also preferred that the phospholipid
solution comprise a phospholipid in propylene glycol.
It is also understood that the present formulations may be used
with other ingredients used with conventional oral formulations
such as, but not limited to, flavor enhancers, coloring agents,
adjuvants, antifungal agents, antibacterial agents, etc.
It is contemplated that when the formulations of this invention are
used as an immunosuppressive or antiinflammatory agent, they can be
administered in conjunction with one or more other immunoregulatory
agents. Such other antirejection chemotherapeutic agents include,
but are not limited to azathioprine, corticosteroids, such as
prednisone and methylprednisolone, cyclophosphamide, cyclosporin A,
FK-506, OKT-3, and ATG. By combining one or more of the
formulations of the present invention with such other drugs or
agents for inducing immunosuppression or treating inflammatory
conditions, lesser amounts of each of the agents may be required to
achieve the desired effect. The basis for such combination therapy
was established by Stepkowski whose results showed that the use of
a combination of rapamycin and cyclosporin A at subtherapeutic
doses significantly prolonged heart allograft survival time.
[Transplantation Proc. 23:507 (1991)].
The formulations of the present invention are exemplified, but not
limited by, the preferred formulations and processes described
below:
EXAMPLES
Example 1
Rapamycin Oral at 1 mg/ml
A rapamycin oral formulation at a concentration of 1 mg/ml can be
formulated from the following active and inactive ingredients by
the procedural steps which follow:
______________________________________ Batch Formula Conc. Input
10,000 bottles ______________________________________ Active
Ingredient: 1.00 mg/ml 0.025 g 0.250 kg Rapamycin @ 100% Inactive
Ingredients: Polysorbate 80, NF 10.8 mg/ml 0.270 g 2.700 kg Phosal
50 PG .RTM. 1.00 ml 25.0 ml 250.0 L propylene glycol and lecithin
q.s. ad or 1.005 gm or 25.125 g 251.25 kg
______________________________________ Density of the Final
Formulation 1.005 g/ml
If the potency of the rapamycin is less than 100%, the input must
be adjusted to achieve the claimed potency.
Method of Manufacture
Procedure:
1. Weigh the rapamycin into a suitable container.
2. Add the Polysorbate 80 to the container in step #1
3. Adjust to the final volume with Phosal 50 PG.
4. Mix until the rapamycin is dissolved.
5. Fill 25 ml.+-.1.25 ml (25.125 g.+-.1.256 g) into each one ounce
amber glass bottle. It is preferable to seal with a child resistant
cap.
For improved wettability and ease of solution, an alternative order
of addition of the ingredients and amounts presented above is as
follows:
1. Polysorbate 80.
2. A portion of the Phosal 50 PG propylene glycol and lecithin.
3. Rapamycin.
4. The remaining Phosal 50 PG propylene glycol and lecithin.
The rapamycin in these formulations may also be comminuted by use
of a mill or mortar and pestle and passed through an 80 mesh
screen.
Example 2
Rapamycin Oral at 5 mg/ml
A rapamycin oral formulation at a concentration of 5 mg/ml can be
formulated from the following active and inactive ingredients by
the procedural steps which follow:
______________________________________ Batch Formula 10,000 Conc.
Input bottles ______________________________________ Active
Ingredient: 5.00 mg 0.125 g 1.250 kg Rapamycin @ 100% Inactive
Ingredients: Polysorbate 80, NF 10.8 mg 0.270 g 2.70 kg Phosal 50
PG 1.00 ml 25.0 ml 250.0 L propylene glycol and lecithin q.s. ad or
1.005 gm or 25.125 g or 251.25 kg
______________________________________ Density of the Final
Formulation 1.005 g/ml.
If the potency of the rapamycin is less than 100%, the input must
be adjusted to give the claimed potency.
The procedural steps for formulation and storage of the 5 mg/ml
oral rapamycin formulation are the same as those listed in Example
1, as are the alternative order of addition of ingredients and the
methods of comminution.
Example 3
The formulation of this Example 3 was produced using the
ingredients which follow and the methods indicated below:
______________________________________ Ingredients Amount
______________________________________ Rapamycin @ 100% up to 1.0
gm Polysorbate 80, NF 1.0 ml or 1.08 gm Phosal 50 PG lecithin and
propylene glycol 100 ml or 100.5 gm q.s.
______________________________________
Method of Formulation
1. Weigh the rapamycin into a suitable container.
2. Add the Polysorbate 80 into the container of Step #1.
3. Adjust to the final volume with Phosal 50 PG.RTM. propylene
glycol and lecithin.
4. Mix until a solution results.
Alternatively, this formula can be packaged in a suitable container
or encapsulated into a capsule.
Cynomolgus monkeys were administered a formulation of Example 3,
above, at a dose of 0.25 mg/kg of rapamycin and the following serum
concentrations were determined at the indicated time after
dosing:
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally as a Dispersion of 0.25 mg/kg Time
Rapamycin Concentrate (.mu.g/ml) (hrs) A B C D E F
______________________________________ 0 0.000 0.000 0.000 0.000
0.000 0.000 .25 0.012 0.001 0.005 0.000 0.000 0.000 .50 0.014 0.000
0.024 0.004 0.000 0.003 1 0.011 0.002 0.021 0.006 0.003 0.004 2
0.005 0.019 0.008 0.004 0.007 0.003 4 0.002 0.006 0.007 0.003 0.006
0.002 8 0.002 0.004 0.005 0.003 0.002 0.001 12 0.001 0.002 0.003
0.002 0.001 0.001 24 0.001 0.002 0.001 0.001 0.002 0.001 36 0.000
0.002 0.001 0.001 0.000 0.000
______________________________________
Example 4
______________________________________ Formula Ingredients
______________________________________ Rapamycin @ 100% up to 2.5
grams Polysorbate 80, NF 5.0 ml or 5.4 gm Absolute Ethanol 12.67 ml
or 10.0 gm Phosal 50 PG lecithin and propylene glycol 100 ml q.s.
______________________________________
This formulation can be produced by the following steps:
1. Weigh the rapamycin into a suitable container
2. Add the absolute ethanol to the container in Step #1. Mix until
dissolved.
3. Add the polysorbate 80 to the container in Step #2. Mix until
uniform.
4. Add Phosal 50 PG lecithin and propylene glycol to adjust to the
final volume.
5. Mix until uniform.
Alternatively, this formula can be packaged in a suitable container
or encapsulated into a capsule.
Cynomolgus monkeys were administered the formulation above at a
dose of 0.25 mg/kg of rapamycin and the following serum
concentrations were determined at the indicated time after
dosing.
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally in a Dispersion at 0.25 mg/kg Rapamycin
Concentration (.mu.g/ml) Time Monkey No. (hr) A B C D E F
______________________________________ 0 0.000 0.000 0.000 0.000
0.000 0.000 .25 -- 0.025 0.007 0.010 0.007 0.003 .50 0.008 0.030
0.027 0.004 0.016 0.012 1 0.050 0.022 0.051 0.006 0.051 0.011 2
0.026 0.026 0.026 0.019 0.025 0.006 4 0.008 0.011 0.020 0.005 0.018
0.006 8 0.008 0.004 0.009 0.003 0.011 0.003 12 0.004 0.002 0.006
0.005 0.007 0.003 24 0.002 -- 0.004 0.002 0.004 0.001 36 0.000
0.003 0.003 0.001 0.003 0.002
______________________________________
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally in SEG Capsules at 0.25 mg/kg Rapamycin
Concentration (.mu.g/ml) Time Monkey No. (hr) A B C D E F
______________________________________ 0 0.000 0.000 0.000 0.000
0.000 0.000 .25 0.000 0.000 0.000 0.000 0.001 0.001 .50 0.000 0.000
0.000 0.000 0.010 0.006 1 0.030 0.013 0.001 0.000 0.019 0.005 2
0.014 0.024 0.014 0.002 0.014 0.005 4 0.013 0.011 0.003 0.006 0.015
0.004 8 0.007 0.004 0.002 0.002 0.007 0.002 12 0.005 0.003 0.001
0.001 0.006 0.001 24 0.003 0.001 0.001 0.001 0.003 0.001 36 0.002
0.001 0.001 0.000 0.001 0.000
______________________________________
Example 5
The oral formulations of this invention, such as those disclosed in
Example 1 above, may also be prepared in encapsulated forms, such
as formulations within starch or SEG capsules. The following
procedure describes a method which may be utilized to prepare such
encapsulated formulations.
Procedure:
1) Add to a container, NF, the Polysorbate 80.
2) Add to the Polysorbate 80 of Step #1 80% of the the required
Phosal 50 PG.
3) Weigh the rapamycin component of the formulation into the
container of Step #2.
4) Adjust to the final formulation weight with Phosal 50 PG.
5) Establish a nitrogen atmosphere over the formulation and
maintain until the capsules are filled.
6) Mix the formulation until the rapamycin is dissolved.
7) Pass the formulation solution through a particulate (such as a
100 mesh screen) or scintered glass filter.
8) Fill 0.50 ml of the Step #7 material into capsule shells using
an automatic syringe dispensing unit and seal the capsule.
9) Package the filled capsules upon completion of encapsulation. An
example of a preferred package is a conventional blister package
with a perforable metal foil backing.
10) Store the finished encapsulated product at refridgerated
conditions (2.degree.-8.degree. C.) protected from light.
The primary capsule sealant for the starch capsule may be a 5%
Dextrin, NF, aqueous solution. It is preferable to heat purified
water to 50.degree.-60.degree. C. prior to compounding to
facilitate dissolution of the Dextrin. Prior to use it is also
preferable to filter the the Dextrin solution through a suitable
particulate filter.
Bioavailability
a) Cynomolgus monkeys were administered a starch and SEG
encapsulated formulation of Example 3, above, at a dose of 0.25
mg/kg of rapamycin and the following serum concentrations were
determined at the indicated time after dosing:
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally in Starch Capsules 0.25 mg/kg Time
Rapamycin Concentrate (.mu.g/kg) (hrs) A B C D E F
______________________________________ 0 0.000 0.000 0.000 0.000
0.000 0.000 .25 0.000 0.000 0.000 0.000 0.000 0.000 .50 0.000 0.000
0.005 0.000 0.005 0.000 1 0.029 0.004 0.026 -- 0.008 0.000 2 0.011
0.019 0.032 0.000 0.011 0.004 4 0.007 0.009 0.011 0.002 0.007 0.002
8 0.004 0.003 0.004 0.002 0.005 0.002 12 0.002 0.001 -- 0.001 0.002
0.001 24 0.001 0.000 0.002 0.001 0.001 0.000 36 0.000 0.000 0.000
0.000 0.000 0.000 ______________________________________
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally in SEG Capsules at 0.25 mg/kg Time (hrs)
A B C D E F ______________________________________ 0 0.000 0.000
0.000 0.000 0.000 0.000 .25 0.005 0.002 0.001 0.001 0.001 0.002 .50
0.001 0.001 0.002 0.002 0.001 0.001 1 0.043 0.022 0.019 0.002 0.003
0.012 2 0.027 0.030 0.019 0.002 0.010 0.008 4 0.012 0.012 0.015
0.009 0.011 0.006 8 0.008 0.006 0.009 0.004 0.006 0.003 12 0.008
0.004 0.006 0.002 0.005 0.002 24 0.006 0.003 0.005 0.001 0.002
0.001 36 0.002 0.001 0.002 0.001 0.002 0.001
______________________________________
b) 3 mg starch encapsulated formulations containing rapamycin at a
concentration of 6 mg/ml, prepared as described above, were
administered to 14 healthy male human volunteers between the ages
of 18 and 45, from whom blood samples were drawn at the time
intervals indicated in the table below. The rapamycin blood samples
were assayed for whole blood rapamycin concentration using a
validated (ESP)-HPLC-MS method.
______________________________________ Time Interval Following
Blood Concentration Administration (Hours) (conc. = ng/ml)
______________________________________ 0.33 0.41 0.67 6.53 1 8.57 2
8.27 3 5.54 4 3.96 5 3.10 8 1.93 12 1.47 18 1.05 24 0.80 48 0.54
______________________________________
COMPARATIVE EXAMPLES
Comparative Example 1
The following Comparative Examples illustrate traditional
solutions, suspensions or emulsions that are used to administer
drugs which have poor water solubilities, and which have now been
applied to the administration of rapamycin, as well as the blood
levels of rapamycin provided by such administrations.
This first standard formulation utilizes a diluent having the
ingredients and made by the steps listed below:
______________________________________ Diluent for Oral Rapamycin
Formulations Ingredients Amounts
______________________________________ Polysorbate 80, NF 5.0 ml
0.5M Citric Acid (pH 4) q.s. 100 ml
______________________________________
Manufacturing Directions
1. Prepare a 0.5M Citric Acid solution.
2. Adjust the pH of the solution in Step #1 to 4.0 using 50% w/w
NaOH.
3. Place the Polysorbate 80 into a suitable container.
4. QS to 100 ml with the solution from step #2.
5. Mix until uniform.
This diluent may be used to create an oral rapamycin formulation by
mixing rapamycin with the diluent as indicated below:
______________________________________ Ingredients Amounts
______________________________________ Rapamycin Micronized @ 100%
up to 5.0 gm Diluent for Oral Rapamycin q.s. 100 ml
______________________________________
Manufacturing Directions
1. Weigh the rapamycin into a suitable container.
2. QS with the diluent for rapamycin.
3. Mix until uniform.
Cynomolgus monkeys were administered the above formulation at a
dose of 50 mg/kg of rapamycin and the following serum
concentrations were determined at the indicated time after
dosing.
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally with 50 mg/kg Rapamycin Oral Suspension
Rapamycin Concentration (.mu.g/ml) Time Monkey No. (hr) A B C
______________________________________ 0 BDL BDL BDL 1 BDL BDL BDL
2 BDL BDL BDL 3 BDL BDL BDL 4 BDL BDL BDL 6 BDL BDL BDL 9 BDL BDL
BDL 12 BDL BDL BDL ______________________________________ BDL =
Below detection limit (detection limit = 0.006 .mu.g/ml)
Comparative Example 2
A second traditional formulation, with rapamycin as the active
ingredient, can be produced by the using the following ingredients
in the steps below:
______________________________________ Rapamycin Oral Ingredients
Amount ______________________________________ Rapamycin @ 100% 5.0
gm Dimethylacetamide 10.0 gm Absolute Ethanol 10.0 gm Miglyol 812
q.s. 100 ml ______________________________________
Procedure:
1. Place rapamycin into a suitable container.
2. Add the dimethylacetamide and ethanol to the container in Step
#1 and mix until a solution results.
3. QS with Miglyol 812 and mix until uniform.
4. Filter sample through a 0.2 micron Teflon filter.
Cynomolgus monkeys were administered this second comparative
formulation at a dose of 50 mg/kg of rapamycin and the following
serum concentrations were determined at the indicated time after
dosing.
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally with 50 mg/kg Rapamycin Oral Solution
Rapamycin Concentration (.mu.g/ml) Time Monkey No. (hr) A B C
______________________________________ 0 BDL BDL BDL 1 BDL BDL BDL
2 BDL BDL BDL 3 BDL BDL BDL 4 BDL BDL BDL 6 BDL BDL BDL 9 BDL BDL
BDL 12 BDL BDL BDL ______________________________________ BDL =
Below detection limit (detection limit = 0.006 .mu.g/ml)
Comparative Example 3
A third comparative formulation was produced using the ingredients
and method described below:
______________________________________ Rapamycin Oral Emulsion at
50 mg/ml Formula: Ingredients Amount
______________________________________ Rapamycin @ 100% 5.0 gm
Dimethylacetamide 10 ml Olive Oil q.s. 100 ml
______________________________________
Procedure:
1. Place the rapamycin into a suitable container.
2. Add the dimethylacetatmide to the container in Step #1 and mix
until clear.
3. QS with Olive Oil and mix until homogenous.
Cynomolgus monkeys were administered this second comparative
formulation at a dose of 50 mg/kg of rapamycin and the following
serum concentrations were determined at the indicated time after
dosing.
______________________________________ Rapamycin Concentration in
Monkey Serum Dosed Orally with 50 mg/kg Rapamycin Oral Emulsion
Rapamycin Concentration (.mu.g/ml) Monkey No. Time A B C
______________________________________ 0 BDL BDL BDL 20 min BDL BDL
BDL 40 min BDL BDL BDL 80 min BDL BDL BDL 3 hr BDL BDL BDL 6 hr BDL
0.110* BDL 12 hr BDL BDL BDL 24 hr BDL BDL BDL
______________________________________ BDL = Below detection limit
(detection limit = 0.006 .mu.g/ml) *NOTE: Assay result obtained
from test lab appears aberent.
* * * * *